title: Asparagine substitution at PB2 residue 701 enhances the replication, pathogenicity, and transmission of the 2009 pandemic H1N1 influenza A virus.
abstract: The 2009/2010 pandemic influenza virus (H1N1pdm) contains an avian-lineage PB2 gene that lacks E627K and D701N substitutions important in the pathogenesis and transmission of avian-origin viruses in humans or other mammals. Previous studies have shown that PB2-627K is not necessary because of a compensatory Q591R substitution. The role that PB2-701N plays in the H1N1pdm phenotype is not well understood. Therefore, PB2-D701N was introduced into an H1N1pdm virus (A/New York/1682/2009 (NY1682)) and analyzed in vitro and in vivo. Mini-genome replication assay, in vitro replication characteristics in cell lines, and analysis in the mouse and ferret models demonstrated that PB2-D701N increased virus replication rates and resulted in more severe pathogenicity in mice and more efficient transmission in ferrets. In addition, compared to the NY1682-WT virus, the NY1682-D701N mutant virus induced less IFN-λ and replicated to a higher titer in primary human alveolar epithelial cells. These findings suggest that the acquisition of the PB2-701N substitution by H1N1pdm viruses may result in more severe disease or increase transmission in humans.
authors.affiliation: J. Craig Venter Institute, Rockville, Maryland, United States of America.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhou
authors.forename: Melissa B
authors.initials: MB
authors.lastname: Pearce
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Jieru
authors.initials: J
authors.lastname: Wang
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mason
authors.forename: Terrence M
authors.initials: TM
authors.lastname: Tumpey
authors.forename: David E
authors.initials: DE
authors.lastname: Wentworth
mesh_terms: D056809:Alveolar Epithelial Cells / Q000276:immunology / Q000821:virology; D019943:Amino Acid Substitution; D000818:Animals; D001216:Asparagine / Q000235:genetics; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D004285:Dogs; D005260:Female; D005289:Ferrets; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000472:pathogenicity / Q000502:physiology*; D007251:Influenza, Human / Q000201:enzymology / Q000635:transmission* / Q000821:virology; D007700:Kinetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D012324:RNA-Dependent RNA Polymerase / Q000235:genetics*; D014764:Viral Proteins / Q000235:genetics*; D014779:Virus Replication / Q000235:genetics*
chemical_list: D016207:Cytokines; C057027:PB2 protein, Influenzavirus A; D014764:Viral Proteins; D001216:Asparagine; D012324:RNA-Dependent RNA Polymerase